The molecular basis and genotype–phenotype correlations of congenital adrenal hyperplasia (CAH) in Anatolian population

Dundar, Ayca; Bayramov, Ruslan; Onal, Muge Gulcihan; Akkuş, Mustafa; Doğan, Muhammet Ensar; Kenanoğlu, Sercan; Gunes, Meltem Cerrah; Kazimli, Ulviye; Özbek, Mehmet Nuri; Ercan, Oya; Yıldırım, Ruken; Çelmeli, Gamze; Parlak, Mesut; Dündar, İsmail; Hatipoğlu, Nihal; Ünlühızarcı, Kürşad; Akalın, Hilal; Özkul, Yusuf; Saatci, Cetin; Dündar, Munis

doi:10.1007/s11033-019-04809-4

Cited by 9 publications

(11 citation statements)

References 58 publications

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“…In our study group, a good correlation between genotype and phenotype was observed in group null (patients with alterations in both alleles resulting in 0% residual enzyme [26,28,[30][31][32][33]. Previous studies reported 100% concordance in null, 80-96% in A, and about 50-87% in B genotypes [13,27,34,35]. In a huge cohort study by New at al., based on 1507 families with CAH, a genotypephenotype non-concordance was observed in 50% of cases [36].…”

Section: Discussionsupporting

confidence: 70%

“…Results of previous studies confirm a good correlation between the genotype and the observed CAH phenotype [ 26 , 28 , 30 – 33 ]. Previous studies reported 100% concordance in null , 80–96% in A, and about 50–87% in B genotypes [ 13 , 27 , 34 , 35 ]. In a huge cohort study by New at al., based on 1507 families with CAH, a genotype-phenotype non-concordance was observed in 50% of cases [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

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Molecular analysis and genotype-phenotype correlations in patients with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency from southern Poland — experience of a clinical center

et al. 2022

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Purpose The prevalence of CYP21A2 gene variants and genotype-phenotype correlations are variable among populations. The aim of this study was to characterize CYP21A2 gene variants in adult patients with classical congenital adrenal hyperplasia (CCAH) from southern Poland and to analyze genotype-phenotype correlations. Materials/Methods A total of 48 patients (30 women and 18 men) with CCAH were included in the study. Patients were divided into two clinical subgroups, namely, salt-wasting (SW) — 38 patients and simple virilizing (SV) — 10 patients. A genetic analysis MLPA (multiplex ligation-dependent probe amplification) was performed in all of them. In dubious cases, the analysis was complemented by Sanger sequencing. Genotypes were classified into five groups (depending on the residual in vitro enzymatic activity), namely, null, A, B, C, and D, and correlated with the clinical picture. Results Molecular defects were investigated and identified in 48 patients. The most common variant in the studied group was I2G, followed by whole or partial gene copy deletion, and I172N. One novel variant c.[878G>T] (p.Gly293Val) was found. In nine patients, a non-concordance between genotype and phenotype was observed. Genotype-phenotype correlations measured by positive predictive value (PPV) were as follows: 100% in group null, 90.5% in group A, and 66.7% in group B. Conclusions CYP21A2 variants in the studied cohort were similar to values previously reported in other countries of the region. There was a good correlation between genotype and phenotype in the null and A groups, the correlation being considerably lower in group B.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Molecular analysis and genotype-phenotype correlations in patients with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency from southern Poland — experience of a clinical center

et al. 2022

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“…We synthetized the studies published according to the mentioned methodology in Table 1 [ 5 , 22 , 25 , 26 , 27 , 31 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ].…”

Section: Methodsmentioning

confidence: 99%

“…Most articles introduce cases with SW forms, which seem like a common presentation due to its severity. The majority of patients were diagnosed after a SW crisis (vomiting, diarrhoea, hyponatremia, hyperkaliaemia, and hypoglycaemia) early during childhood or soon after birth [ 22 , 25 , 26 , 31 , 38 , 40 , 41 , 43 , 44 , 47 , 50 , 53 , 55 , 57 , 58 ]. Other signs and symptoms that are described under these circumstances are a lack of sweating, malnutrition, and developmental delay [ 31 , 50 ].…”

Section: Methodsmentioning

confidence: 99%

Approach of Heterogeneous Spectrum Involving 3beta-Hydroxysteroid Dehydrogenase 2 Deficiency

et al. 2022

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We aim to review data on 3beta-hydroxysteroid dehydrogenase type II (3βHSD2) deficiency. We identified 30 studies within the last decade on PubMed: 1 longitudinal study (N = 14), 2 cross-sectional studies, 1 retrospective study (N = 16), and 26 case reports (total: 98 individuals). Regarding geographic area: Algeria (N = 14), Turkey (N = 31), China (2 case reports), Morocco (2 sisters), Anatolia (6 cases), and Italy (N = 1). Patients’ age varied from first days of life to puberty; the oldest was of 34 y. Majority forms displayed were salt-wasting (SW); some associated disorders of sexual development (DSD) were attendant also—mostly 46,XY males and mild virilisation in some 46,XX females. SW pushed forward an early diagnosis due to severity of SW crisis. The clinical spectrum goes to: premature puberty (80%); 9 with testicular adrenal rest tumours (TARTs); one female with ovarian adrenal rest tumours (OARTs), and some cases with adrenal hyperplasia; cardio-metabolic complications, including iatrogenic Cushing’ syndrome. More incidental (unusual) associations include: 1 subject with Barter syndrome, 1 Addison’s disease, 2 subjects of Klinefelter syndrome (47,XXY/46,XX, respective 47,XXY). Neonatal screening for 21OHD was the scenario of detection in some cases; 17OHP might be elevated due to peripheral production (pitfall for misdiagnosis of 21OHD). An ACTH stimulation test was used in 2 studies. Liquid chromatography tandem–mass spectrometry unequivocally sustains the diagnostic by expressing high baseline 17OH-pregnenolone to cortisol ratio as well as 11-oxyandrogen levels. HSD3B2 gene sequencing was provided in 26 articles; around 20 mutations were described as “novel pathogenic mutation” (frameshift, missense or nonsense); many subjects had a consanguineous background. The current COVID-19 pandemic showed that CAH-associated chronic adrenal insufficiency is at higher risk. Non-adherence to hormonal replacement contributed to TARTs growth, thus making them surgery candidates. To our knowledge, this is the largest study on published cases strictly concerning 3βHSD2 deficiency according to our methodology. Adequate case management underlines the recent shift from evidence-based medicine to individualized (patient-oriented) medicine, this approach being particularly applicable in this exceptional and challenging disorder.

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“…Rare pathogenic variants were also found that included c.549+1G>A and c.499G>C. 17 of the variants were reported before (Bidet et al, 2009;New et al, 2013;Hong et al, 2015;Wang et al, 2016;Concolino and Costella, 2018; Concentration data are presented as the median (range). Dundar et al, 2019). One novel mutation of small deletion was detected, g.732_897del166bp, which leads to partial deletion of exon 3 and intron 3 and suspected pathogenic mutation while the specific functional impact is unknown yet (Figure 3; Supplementary Figure 1).…”

Section: Cyp21a2 Mutation Spectrum Analysismentioning

confidence: 99%

Neonatal Screening and Genotype-Phenotype Correlation of 21-Hydroxylase Deficiency in the Chinese Population

Wang

et al. 2021

Front. Genet.

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Background: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway that leads to impaired cortisol biosynthesis. 21-hydroxylase deficiency (21-OHD) is the most common type of CAH. Severe cases of 21-OHD may result in death during the neonatal or infancy periods or sterility in later life. The early detection and timely treatment of 21-OHD are essential. This study aimed to summarize the clinical and genotype characteristics of 21-OHD patients detected by neonatal screening in Nanjing, Jiangsu province of China from 2000 to 2019.Methods: Through a retrospective analysis of medical records, the clinical presentations, laboratory data, and molecular characteristics of 21-OHD patients detected by neonatal screening were evaluated.Results: Of the 1,211,322 newborns who were screened, 62 cases were diagnosed with 21-OHD with an incidence of 1:19858. 58 patients were identified with the classical salt-wasting type (SW) 21-OHD and four patients were identified with simple virilizing type (SV) 21-OHD. Amongst these patients, 19 cases patients accepted genetic analysis, and another 40 cases were received from other cities in Eastern China. Eighteen different variants were found in the CYP21A2 gene. The most frequent variants was c.293-13A/C>G (36.29%). The most severe clinical manifestations were caused by large deletions or conversions of CYP21A2.Conclusions: This study suggested that neonatal screening effectively leads to the early diagnosis of 21-OHD and reduces fatal adrenal crisis. Our data provide additional information on the occurrence and genotype-phenotype correlation of 21-OHD in the Chinese population which can be used to better inform treatment and improve prognosis.

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The molecular basis and genotype–phenotype correlations of congenital adrenal hyperplasia (CAH) in Anatolian population

Cited by 9 publications

References 58 publications

Molecular analysis and genotype-phenotype correlations in patients with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency from southern Poland — experience of a clinical center

Molecular analysis and genotype-phenotype correlations in patients with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency from southern Poland — experience of a clinical center

Approach of Heterogeneous Spectrum Involving 3beta-Hydroxysteroid Dehydrogenase 2 Deficiency

Neonatal Screening and Genotype-Phenotype Correlation of 21-Hydroxylase Deficiency in the Chinese Population

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